Head injured patients are hypermetabolic, hypercatabolic, hyperdynamic, and manifest the a cute phase response. They have elevations of classic counter-regulatory hormones (e.g., catecholamines) which play an important role in the metabolic response to brain injury. These patients also have marked elevations in serum and ventricular fluid cytokines interleukin-1, tumor necrosis factor, and interleukin-6 as well as decreased plasma levels of the anabolic hormone insulin-like growth factor-1 (IGF-I). Many of the metabolic effects of cytokines also are clinical consequences of head injury (e.g., fever, neutrophilia, muscle catabolism, and increased hepatic acute phase reactants). We have [postulated that an imbalance between increases in proinflammatory catabolic cytokines and inadequate concentrations of the anabolic hormone IGF-I lead to many of the metabolic consequences of head injury. It is our hypothesis that the liver, the largest reservoir of tissue macrophages in the body, plays an important role in the increased cytokines and cytokine mediated complications/manifestations of head injury. In this study, we will use the electronically controlled pneumatic impactor rat model of brain injury to quantitate the time course and extent of increased cytokine production following head injury, the role of the liver and peripheral blood mononuclear cells in cytokine production, the time course and depression of IGF-I production, and the role of gut-derived endotoxin in stimulating these metabolic events. We next will evaluate the effects of brain injury on the development of liver injury and cholestasis using in vivo, in vitro, and isolated perfused liver models. We will investigate two potentially interactive mechanisms for increased cytokine production after brain injury: 1) increased intestinal permeability to gut-derived toxins which stimulate cytokines, 2) impaired Kupffer cell clearance of toxins which stimulate peripheral mononuclear cell cytokine production. Next, we will determine whether head injury, with increased cytokine activity and impaired RE function, predisposes to lethality in a model of sepsis. Finally, extensive preliminary data from our laboratory indicate that both brain injury and cytokines markedly alter the expression and regulation of hepatic drug metabolizing enzymes. Therefore, we will evaluate the effect of isolated brain injury in the rat on hepatic drug metabolism using molecular biology techniques in vitro as well as in vivo drug metabolism assays. These studies will provide new insights into the role of the liver in the metabolic a abnormalities/complications following head injury. Potential new therapies for these metabolic abnormalities/complications (e.g.,cytokine inhibition and growth factors) are available for testing in our model systems, and they may provide unique management options for head injured patients in the near future.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
United States
Zip Code
Gebregziabher, Mulugeta; Hoel, David (2009) Applications of the Poly-K Statistical Test to Life-Time Cancer Bioassay Studies. Hum Ecol Risk Assess 15:858-875
Hatton, Jimmi; Kryscio, Richard; Ryan, Melody et al. (2006) Systemic metabolic effects of combined insulin-like growth factor-I and growth hormone therapy in patients who have sustained acute traumatic brain injury. J Neurosurg 105:843-52
Scheff, S W; Price, D A; Hicks, R R et al. (2005) Synaptogenesis in the hippocampal CA1 field following traumatic brain injury. J Neurotrauma 22:719-32
Sullivan, Patrick G; Rabchevsky, Alexander G; Keller, Jeffery N et al. (2004) Intrinsic differences in brain and spinal cord mitochondria: Implication for therapeutic interventions. J Comp Neurol 474:524-34
Dempsey, Robert J; Raghavendra Rao, Vemuganti L (2003) Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg 98:867-73
Raghavendra Rao, Vemuganti L; Bowen, Kellie K; Dhodda, Vinay K et al. (2002) Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. J Neurochem 83:1072-86
Guo, Jun-Tao; Yu, Jin; Grass, David et al. (2002) Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis. J Neurosci 22:5900-9
Adibhatla, Rao Muralikrishna; Hatcher, James F; Sailor, Kurt et al. (2002) Polyamines and central nervous system injury: spermine and spermidine decrease following transient focal cerebral ischemia in spontaneously hypertensive rats. Brain Res 938:81-6
Rao, V L; Dogan, A; Bowen, K K et al. (2001) Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain. Eur J Neurosci 13:119-28
Rao, V L; Bowen, K K; Rao, A M et al. (2001) Up-regulation of the peripheral-type benzodiazepine receptor expression and [(3)H]PK11195 binding in gerbil hippocampus after transient forebrain ischemia. J Neurosci Res 64:493-500

Showing the most recent 10 out of 68 publications